The overall goal of this grant, which has been revised for a second time, is to take a novel approach, using a nonhuman primate model, to identify genes that may underlie the development of two common psychiatric illnesses, anxiety and depression. These disorders are common psychiatric illnesses of both childhood and adulthood, that are highly comorbid and strongly aggregate within families, with the same genes affecting liability to both kinds of disorders. The commonness and complex nature of these disorders, however, argue it will be difficult to determine their genetic underpinnings. Special study designs may be required to make serious headway. One such design, proposed here, examines the neurobehavioral genetics of young rhesus monkeys. Specifically, we plan to study the genetic underpinnings of behaviors in rhesus monkeys that parallel several interrelated behavioral and temperamental traits linked to anxiety disorders and depression in humans, including fearfulness, behavioral inhibition, propensity towards distress, and reactivity. In addition, we will evaluate the genetic basis of a physiological attributes associated with anxiety and depression, specifically blunted growth hormone (GH) responsiveness to pharmacological stimulation, activity of the HPA axis, and CSF neurotransmitter levels. This proposal is particularly timely in that increased evidence supporting these behavioral and physiological measures as markers of an underlying predisposition to develop anxiety and depression in humans has recently been published, and we have recently found that in young infant rhesus monkeys there is a strong correlation between low GH responsiveness and behavioral inhibition, and that these measures show a high degree of heritability. The specific aims of the grant include (1) phenotyping a large kindred of rhesus monkeys using four standardized human tests of anxious, fearful and inhibited behaviors, and a clinical protocol for testing GH and CRH responsiveness to stimulation, and measuring CSF monoamine metabolite levels, (2) a genome-wide scan using 300 QTLs, (3) identification of candidate linkage regions, and (4) screening candidate genes. This project has been developed as a collaborative effort between investigators at three institutions, in order to bring together a team with expertise in assessment of nonhuman primate behavior and physiological measurements, QTL analysis in nonhuman primates, and large scale genomics research.